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Bioequivalence, Efficacy, and Safety

SYMPAZAN® is proven bioequivalent to clobazam tablets1,2

Bioequivalence

SYMPAZAN is proven bioequivalent to clobazam tablets1,2

Mean Plasma Concentration Profiles: SYMPAZAN vs. Clobazam Tablets2

Plasma Concentration (ng/ml)

  • SYMPAZAN 20 mg Oral Film
  • Clobazam 20 mg Tablet
  • SYMPAZAN 10 mg Oral Film
  • Clobazam 10 mg Tablet

SYMPAZAN oral film reached max concentration in as little as 20 minutes (Tmax: Median 1.5 hrs, Min 20 min, Max 4 hrs)

Nominal Time (hours)

In a single-dose, open-label, randomized, 4-period, 4-sequence, 4-treatment, crossover pharmacokinetic study with 51 healthy subjects, SYMPAZAN demonstrated bioequivalence to clobazam tablets.2

Efficacy

In a controlled clinical study, as adjunctive treatment, clobazam, the active ingredient in SYMPAZAN, reduced weekly drop seizures from 41%-68% in patients with LGS.1*

Mean Percent Reduction From Baseline in Weekly Drop-Seizure Frequency

Percentage (%) Reduction in
Weekly Drop-Seizure Rates

P<0.05P<0.01P<0.01

SYMPAZAN was not used in this study

Placebo (N=57)
Low-dosage clobazam (N=53)

(5 mg/day in pts ≤30 kg;
10 mg/day in pts >30 kg)

Medium-dosage clobazam (N=58)

(10 mg/day in pts ≤30 kg;
20 mg/day in pts >30 kg)

High-dosage clobazam (N=49)

20 mg/day in pts ≤30 kg;
40 mg/day in pts >30 kg)

The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to the 12-week maintenance period.1

*Study 1 (N=238) was a randomized, double-blind, placebo-controlled study consisting of a 4-week baseline period followed by a 3-week titration period and 12-week maintenance period. Patients age 2-54 years with a current or prior diagnosis of LGS were stratified into 2 weight groups (12.5 kg to ≤30 kg or >30 kg) and then randomized to placebo or 1 of 3 target maintenance doses of clobazam. There was no evidence that tolerance to the therapeutic effect of clobazam developed during the 3-month maintenance period.1

Adverse Reactions

The following adverse events have been reported in a clinical trial (Study 1) of patients treated with clobazam, the active ingredient of SYMPAZAN. Adverse reactions that occurred at least 10% more frequently than placebo in any clobazam dose included constipation, somnolence or sedation, pyrexia, lethargy, and drooling.1

Adverse Reactions Reported for ≥5% of Patients and More Frequently Than Placebo in Any Clobazam Treatment Group:1

Adverse Reactions Reported for ≥5% of Patients and More Frequently Than Placebo in Any Clobazam Treatment Group:1

Clobazam Dose Level

Placebo
N=59
%
Lowa
N=58
%
Mediumb
N=62
%
Highc
N=59%
%
All Clobazam
N=179
%
Gastrointestinal Disorders
  • Vomiting
  • Constipation
  • Dysphagia
  • 5
  • 0
  • 0
  • 9
  • 2
  • 0
  • 5
  • 2
  • 0
  • 7
  • 10
  • 5
  • 7
  • 5
  • 2
General Disorders and Administration Site Conditions
  • Pyrexia
  • Irritability
  • Fatigue
  • 3
  • 5
  • 2
  • 17
  • 3
  • 5
  • 10
  • 11
  • 5
  • 12
  • 5
  • 3
  • 13
  • 7
  • 5
Infections and Infestations
  • Upper respiratory tract infection
  • Pneumonia
  • Urinary tract infection
  • Bronchitis
  • 10
  • 2
  • 0
  • 0
  • 10
  • 3
  • 2
  • 2
  • 13
  • 3
  • 5
  • 0
  • 14
  • 7
  • 5
  • 5
  • 12
  • 4
  • 4
  • 2
Metabolism and Nutrition Disorders
  • Decreased appetite
  • Increased appetite
  • 3
  • 0
  • 3
  • 2
  • 0
  • 3
  • 7
  • 5
  • 3
  • 3
Nervous System Disorders
  • Somnolence or sedation
  • Somnolence
  • Sedation
  • Lethargy
  • Drooling
  • Ataxia
  • Psychomotor hyperactivity
  • Dysarthria
  • 15
  • 12
  • 3
  • 5
  • 3
  • 3
  • 3
  • 0
  • 17
  • 16
  • 2
  • 10
  • 0
  • 3
  • 3
  • 2
  • 27
  • 24
  • 3
  • 5
  • 13
  • 2
  • 3
  • 2
  • 32
  • 25
  • 9
  • 15
  • 14
  • 10
  • 5
  • 5
  • 26
  • 22
  • 5
  • 10
  • 9
  • 5
  • 4
  • 3
Psychiatric Disorders
  • Aggression
  • Insomnia
  • 5
  • 2
  • 3
  • 2
  • 8
  • 5
  • 14
  • 7
  • 8
  • 5
Respiratory Disorders
  • Cough
  • 0
  • 3
  • 5
  • 7
  • 5

aMaximum daily dose of 5 mg for ≤30 kg body weight; 10 mg for >30 kg body weight.
bMaximum daily dose of 10 mg for ≤30 kg body weight; 20 mg for >30 kg body weight.
cMaximum daily dose of 20 mg for ≤30 kg body weight; 40 mg for >30 kg body weight.

Two double-blind studies of clobazam tablets in patients with LGS (Study 1 and 2)1 were conducted. Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on clobazam at several doses to placebo.

Important Safety Information

Important Safety Information

INDICATIONS AND USAGE

SYMPAZAN® (clobazam) oral film, CIV is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older.

IMPORTANT SAFETY INFORMATION FOR SYMPAZAN

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS

  • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.
  • The use of benzodiazepines, including SYMPAZAN, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing SYMPAZAN and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction.
  • Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue SYMPAZAN.

CONTRAINDICATIONS

SYMPAZAN is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients.

WARNINGS AND PRECAUTIONS
Risks from Concomitant Use with Opioids

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe SYMPAZAN concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use. Advise both patients and caregivers about the risks of respiratory depression and sedation when SYMPAZAN is used with opioids.

Abuse, Misuse, and Addiction

Abuse and misuse of benzodiazepines often (but not always) involves the use of doses greater than the maximum recommended dosage and commonly involves concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death.

Use of SYMPAZAN, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of SYMPAZAN along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of Central Nervous System (CNS) depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

Dependence and Withdrawal Reactions

Patients at an increased risk of withdrawal reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages and those who have had longer durations of use.

The continued use of benzodiazepines, including SYMPAZAN, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures). In some cases, benzodiazepine users have developed protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months.

Potentiation of Sedation from Concomitant Use with Central Nervous System (CNS) Depressants SYMPAZAN has a CNS depressant effect. Caution patients and/or caregivers against simultaneous use with other CNS depressants or alcohol as the effects of other CNS depressants or alcohol may be potentiated.

Somnolence or Sedation SYMPAZAN causes dose-related somnolence and sedation, which generally begins within the first month of treatment and may diminish with continued treatment. Monitor patients for somnolence and sedation, particularly with concomitant use of other CNS depressants. Caution patients against engaging in hazardous activities requiring mental alertness, i.e., operating dangerous machinery or motor vehicles, until the effect of SYMPAZAN is known.

Serious Dermatological Reactions Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam in both children and adults. Discontinue SYMPAZAN at the first sign of rash, unless the rash is clearly not drug-related.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including clobazam. These events can be fatal or life-threatening, particularly if diagnosis and treatment do not occur as early as possible. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement. Eosinophilia is often present. If such signs or symptoms are present, the patient should be evaluated immediately. SYMPAZAN should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including SYMPAZAN, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Neonatal Sedation and Withdrawal Syndrome Use of SYMPAZAN late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to SYMPAZAN during pregnancy or labor for signs of sedation and monitor neonates exposed to SYMPAZAN during pregnancy for signs of withdrawal; manage these neonates accordingly.

ADVERSE REACTIONS

Adverse reactions (≥10% and more frequently than placebo) included constipation, somnolence or sedation, pyrexia, lethargy, and drooling.

DRUG INTERACTIONS

Opioids: The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression. Limit dosage and duration of concomitant use of benzodiazepines and opioids and follow patients closely for respiratory depression and sedation.
CNS Depressants and Alcohol: Concomitant use of SYMPAZAN with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence. Caution patients and/or caregivers against simultaneous use with other CNS depressants or alcohol, as effects of other CNS depressants or alcohol may be potentiated.
Hormonal Contraceptives: Hormonal contraceptives that are metabolized by CYP3A4: Effectiveness may be diminished when given with SYMPAZAN. Additional non-hormonal forms of contraception are recommended when using SYMPAZAN.
Drug Metabolized by CYP2D6: SYMPAZAN inhibits CYP2D6, therefore dose adjustment may be necessary of drugs metabolized by CYP2D6 when co-administered with SYMPAZAN.
Strong and Moderate Inhibitors of CYP2C19: Dosage adjustment of SYMPAZAN may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole).
Cannabidiol: Coadministration of cannabidiol and SYMPAZAN may increase the risk of SYMPAZAN-related adverse reactions. Consider dose reduction of cannabidiol or SYMPAZAN should this occur.

USE IN SPECIFIC POPULATIONS

Pregnancy: Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal. Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to SYMPAZAN during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, feeding problems, or signs of withdrawal. Manage these neonates accordingly. Encourage pregnant women taking SYMPAZAN to call the toll-free number 1-888-233-2334 to enroll in the Pregnancy Registry or visit http://www.aedpregnancyregistry.org/

Lactation: SYMPAZAN is excreted in human milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. Infants exposed to SYMPAZAN should be monitored for these effects. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYMPAZAN and any potential adverse effects on the breastfed infant from SYMPAZAN or from the underlying maternal condition.

OVERDOSAGE

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal. Employ general supportive measures, including intravenous fluids and airway maintenance for overdosage management. Flumazenil, a specific benzodiazepine receptor antagonist, can lead to withdrawal and adverse reactions, including seizures. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

Please see Full Prescribing Information, including BOXED WARNING and Patient Information at https://www.sympazan.com/pdfs/pi.pdf

To report SUSPECTED ADVERSE REACTIONS, contact Assertio Therapeutics at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

References
1. SYMPAZAN [package insert]. Aquestive Therapeutics; 2024. 2. Integrated Clinical and Statistical Report. A pivotal, open-label, randomized, single-dose, four-period, four-arm, crossover, comparative bioavailability study of clobazam 20 mg and 10 mg oral films and ONFI® 20 mg and 10 mg tablets in healthy male and female volunteers under fasting conditions; August 2017. 3. ONFI. Package insert. Lundbeck; 3/2024.

Program Terms, Conditions, and Eligibility Criteria for the SYMPAZAN Savings Card

1. This offer is valid only for patients 2 years of age or older and is good for use only with a valid prescription for SYMPAZAN (clobazam) oral film at the time the prescription is filled by the pharmacist and dispensed to the patient. 2. Depending on your insurance coverage, most eligible patients may pay as little as $0 per 30-day supply. Check with your pharmacist for your co-pay discount. Maximum savings limit applies; patient out-of-pocket expense may vary. 3. This offer is not valid for use by patients enrolled in Medicare, Medicaid, or other federal or state programs (including any state pharmaceutical assistance programs), or private indemnity or HMO insurance plans that reimburse you for the entire cost of your prescription drugs. Patients may not use this card if they are Medicare-eligible and enrolled in an employer-sponsored health plan or prescription-drug–benefit program for retirees. This offer is not valid for cash-paying patients. 4. Aquestive reserves the right to rescind, revoke, or amend this offer without notice. 5. Offer good only in the USA at participating retail pharmacies. 6. Void if prohibited by law or taxed. 7. This card is not transferable. The selling, purchasing, trading, or counterfeiting of this card is prohibited by law. 8. This card has no cash value and may not be used in combination with any other discount, coupon, rebate, free trial, or similar offer for the specified prescription. 9. This offer is not health insurance. 10. By redeeming this card, you acknowledge that you are an eligible patient and that you understand and agree to comply with the terms and conditions of this offer.

For questions about the program, including savings on mail order prescriptions, please call customer service at 1-844-320-8059.